1. Field of the Invention
The present invention relates to a pharmaceutical composition for preventing or treating pulmonary fibrosis. More particularly, the present invention relates to a pharmaceutical composition for preventing or treating pulmonary fibrosis comprising an isothiocyanate-based compound and a biguanide agent as active ingredients, a method for preventing or treating pulmonary fibrosis using the composition, and use of the isothiocyanate-based compound and the biguanide agent for the preparation of the prophylactic or therapeutic agent for preventing or treating pulmonary fibrosis.
2. Description of the Related Art
Idiopathic pulmonary fibrosis (IPF) is a chronic disease without any apparent etiology, characterized by a progressive fibrosis of the lung interstitium. This disease is generally confined to the lung and has the histological pattern of usual interstitial pneumonia (UIP). There are differences between reports, but this disease is known to have a prevalence of 2-29 cases per 100,000 individuals. In Korea, IPF is designated as one of the rare and intractable diseases, and its clinical coarse is variable. Generally, IPF progresses to respiratory failure with a slowly progressive decline in lung function, and is a fatal disease with a median survival time of 2-3 years from the time of diagnosis. For this reason, many attempts have been made to reveal the exact pathogenesis and etiology of IPF and to develop a therapeutic agent, but no effective therapeutic agents are available so far.
The pathogenesis of IPF is still unclear, but current concepts suggest that repetitive damage of alveolar epithelial cells is followed by an aberrant healing response, resulting in pulmonary fibrosis. The damage to alveolar epithelial cells resulting from various stimulations is not easily regenerated, and aberrant activation of myofibroblasts occurs during the healing process of the damage, leading to excessive production of extracellular matrix and consequently, interstitial pulmonary fibrosis. Once this pathological mechanism was revealed, the use of anti-fibrotic agents was attempted rather than anti-inflammatory agents which were considered as a classical IPF therapy. If has been also suggested that increased oxidative stress is one of the important causes of IPF, which was demonstrated in many pulmonary fibrosis-induced experimental models. An antioxidant N-acetylcysteine is also considered as a therapeutic drug for IPF, although there are restrictions on the use thereof.
According to the 2011 ATS/ERS/JRS/ALAT guidelines for IPF, a combination therapy of an immunosuppressant azathioprine and an anti-inflammatory agent corticosteroid rather increases mortality. Thus, N-acetylcysteine monotherapy or treatment with anticoagulation or pirfenidione (anti-inflammatory, anti-fibrotic, and antioxidant effects) may be a reasonable choice in the minority of patients with IPF. In addition, long-term oxygen treatment or lung transplantation is recommended in the case of chronic respiratory failure. None of the representative anti-inflammatory agents such as corticosteroid or immunosuppressants such as azathioprine, cyclosporin A, and cyclophosphamide are recommended for the treatment. Further, IFN-γ and bosentan have been tried as an anti-fibrotic agent and did not show therapeutic effects. There is a need for a new therapeutic agent for IPF which exhibits various action mechanisms such as anti-inflammatory, anti-fibrotic, and antioxidant effects rather than one action mechanism.
The present inventors have made many efforts to develop a pharmaceutical composition capable of exhibiting a specific prophylactic or therapeutic effect on pulmonary fibrosis. As a result, they found that a combined formulation of an isothiocyanate-based compound, sulforaphane and a biguanide agent, metformin, shows a therapeutic effect on pulmonary fibrosis, thereby relatively completing the present invention.